PI3Ks are a family of related intracellular signal transducer capable of phosphorylating the 3 position hydroxyl group of the inositol ring of Phosphatidylinositol (PtdIns). They are also known as phosphatidylinositol-3-kinases. The pathway, with oncogene PIK3 and tumor suppressor (PTEN) gene is implicated in insensitivity of cancer tumors to insulin and IGF1, in calorie restriction. 3-kinase (PI3K) signaling pathway is a newly identified strategy for the discovery and development of certain therapeutic agents. Among the various subtypes of PI3K, class IA PI3K-alpha has gained increasing attention as a promising drug target for the treatment of cancer due to its frequent mutations and amplifications in various human cancers. In contrast with cytotoxic agents that do not differentiate between normal proliferating and tumour cells, targeted therapies primarily exert their action in cancer cells. Initiation and maintenance of tumours are due to genetic alterations in specific loci. The identification of the genes in these alterations occurs has opened new opportunities for cancer treatment. The PI3K (phosphoinositide 3-kinase) pathway is often overactive in human cancers and various genetic alteration have been found to cause this. In all cases, PI3K inhibition is considered to be one of the most promising targeted therapies for cancer treatment.
Owing to its widespread activation in inflammation and cancer, a growing appreciation of the therapeutic potential of inhibitors of the phosphoinositide 3-kinase (PI3K) pathway has stimulated intense interest in compounds with suitable pharmacological profiles. These are primarily directed toward PI3K itself. However, as class I PI3Ks are also essential for a range of normal physiological processes, broad spectrum PI3K inhibition could be poorly tolerated.
In recent years, patents describing a new generation of PI3K inhibitors have started to appear, with a particular focus on the development of compounds with enhanced isoform selectivity for use as anti-cancer and anti-inflammatory therapies. However, challenges remain for the efforts to pharmacologically target this enzyme family in a successful manner.
Rationale for the Selection of Phosphoinositide 3-Kinase-α (PI3K-α/β) Inhibitors:—
At cellular level, phosphoinositide-3-kinase signaling contributes to many processes, including cell cycle progression, cell growth, survival and migration and intracellular vesicular transport. The PI3K represents the family of lipid kinases that can be classified into three subfamilies according to structure and substrate specificity viz., class I, class II and class III. The class I PI3Ks are the most extensively studied among lipid kinases, are heterodimeric proteins; each containing a smaller regulatory domain and a larger 110 kDa catalytic domain, which occur in four isoforms differentiated as p110α, p110β, p110γ, and p110δ. Although, there are natural product based small molecules reported in the literature which inhibit the PI3-kinases having the IC50 value in nano-gram range (viz., Wortmannin isolated from Penicillium wortmanni, LY294002 a synthetic analogue of the flavonoid quercetin, etc) but these molecules did not reach to market because of low potency, poor isoform or kinase selectivity, limited stability and unacceptable pharmacological and pharmacokinetic properties. However, PI3 kinase inhibitors having isoform selectivity and promising drug-like properties have now begun to emerge that show promise for the treatment of cancer and other disease indications. In cancer, evidence suggests that inhibition of the class 1A PI3 kinases p110α and p110β appear to be the most appropriate to target. Recently, Andersen et al., in 2006 reported the potential isoform selective PI3K-alpha inhibitor from marine sponge Aka coralliphaga under the collaborative program to screen marine invertabrates against human PI3K-alpha keeping in mind that natural products from marine resources have emerged as a copious repository of molecular diversity and hold considerable promise as a rich source of lead structures in drug discovery. Liphagal (Joshua J. Day, Ryan M. McFadden; The catalytic enantioselective total synthesis of (+)-Liphagal; Angew. Chem. Int. Ed. 2011, 50, 6814-6818; Enrique Alvarez-Manzaneda, RachidChahboun; Enantioselectivetotal synthesis of the selective PI3-kinase inhibitor Liphagal; Org. Lett., 2010, 12 (20), pp 4450-4453; Jonathan H. George, Jack E. Baldwin; Enantiospecific biosynthetically inspired formal total synthesis of (+)-Liphagal, Org. Lett., 2010, 12 (10), pp 2394-2397; Alban R. Pereira, Wendy K. Strangman, Synthesis of phosphatidylinositol 3-kinase (PI3K) inhibitory analogues of the sponge meroterpenoid Liphagal; J. Med Chem., 2010, 53 (24), pp 8523-8533; Dima A. Sabbah, Jonathan L. Vennerstrom; Docking studies on isoform-specific inhibition of phosphoinositide-3-kinases; J. Chem. Inf. Model., 2010, 50 (10), pp 1887-1898; Ram Vishwakarma and Sanjay Kumar; Efficient Synthesis of key intermediate toward Liphagal synthesis; Synthetic Communications; 2010, 41(2), pp 177-183; Frederic Marion, David E. Williams, Liphagal, a selective inhibitor of PI3 kinase-α isolated from the sponge Aka coralliphaga: Structure elucidation and biomimetic synthesis; Org. Lett., 2006, 8 (2), pp 321-324; Goverdhan Mehta, Nachiket S. Likhite, C. S. Ananda Kumar A concise synthesis of the bioactive meroterpenoid natural product (±)-liphagal, a potent PI3K inhibitor, Tet. Lett, 2009, vol. 50, no. 37, pp 321-324) was ˜10-fold more potent against PI3K-α than against PI3K-γ. We have synthesized boron containing analog of liphagal by rational modification on this molecule following diversity oriented synthesis approach for the discovery of lead molecules.